1. Field of the Invention
The current invention concerns generally a vaginal or buccal administration of therapeutic agents having a substrate affinity for metabolic cytochrome P-450 enzymes and membrane efflux transporter systems. In particular, the invention concerns a method for augmentation of intraepithelial and/or systemic exposure to the therapeutic agents having a substrate affinity for cytochrome P-450 enzymes and membrane efflux transporter systems, by delivering said agents to the vaginal or oral cavity.
2. Background and Related Disclosures
Cancer and HIV/AIDS viral diseases have become a worldwide problem that needs attention of the medical community.
More than 53 million people worldwide are infected with the HIV/AIDS virus. The dramatically increased incidence of viral infections among women is particularly worrisome because of its risk of infecting unborn children in-utero and consequently posing as one of the major causes for spread of HIV/AIDS.
Cancer has also become one of the leading causes of death worldwide and with decreasing death rates from heart disease in almost all populations it is or will soon become the largest cause of death in the worldwide population.
Facing the increasing risk of spread of the HIV virus, a number of new pharmaceuticals for effective prevention, treatment, control and management of HIV/AIDS has been developed in the past decade. These new pharmaceuticals encompass new drug classes having different biological, physical and/or chemical properties. The new drug classes include, for example and among others, nucleoside analogs, reverse transcriptase inhibitors and HIV protease inhibitors. In many cases, drug cocktails prepared of at least three different drugs of the same or different classes need to be given to a patient to achieve a therapeutic effect. The cost of these treatments is high and exceeds, according to the World Health Organization figures, $3,000 per year/patient.
Similarly, in the past two decades, the major improvement in the treatment of cancer has been achieved with a development of the new cytostatic and/or cytotoxic agents for both the eradication of cancer and/or for inhibiting and limiting its metastatic capabilities. As in a case of the HIV infections, in most cases, a combination of several drugs is administered in order to gain full therapeutic effects.
It has been long known and recognized that systemic exposure of a drug administered via the oral route is quantitatively limited by the intrinsic aqueous solubility, intestinal membrane permeability as well as by hepatic elimination. To improve the efficiency of the drug development and to recommend methods for drug classification according to their bioavailability, various drugs were defined by their aqueous solubility and intestinal membrane permeability using the Biopharmaceutical Classification System (Amidon et al., Pharm. Res., 12: 413-420 (1995)) into four categories designated Class I-IV. Class I drugs have high permeability and high solubility. Class II drugs have high permeability and low solubility. Class III drugs have low permeability and high solubility. Class IV drugs have low permeability and low solubility.
Consequently, the Class I drugs that have both high aqueous solubility and intestinal membrane permeability have also high bioavailability. On the other hand, Classes II-IV have low, often unacceptably low bioavailability depending on the degree of their solubility and/or permeability. The lowest bioavailability have drugs classified in Class IV.
Typically, in a number of drugs classified in the drug classes II-IV, only a minor fraction of the dose administered into the gastrointestinal tract finally reaches the systemic circulation. Pharmacokinetically, this is defined as limited or low oral bioavailability. Such low oral bioavailability is particularly observed for drugs widely used in the treatment of HIV/AIDS and a wide variety of cancers.
Many anti-cancer drugs and HIV therapeutics have the ability to induce molecular regulation mechanisms common to metabolizing enzymes and efflux systems in intestinal cells and the liver that lead to an increased expression of these proteins. As a result, efficacy of drug therapy decreases after some time due to drug-induced efflux activity and metabolic activities. This can lead to greater variability in patient treatment and even to subtherapeutic drug levels, which may enhance development of drug resistance, a phenomenon that is clinically associated with greater therapy failure. The above mentioned drug-induced regulatory pathways are expected to have a minimal impact on systemic drug levels following vaginal and buccal administration due to the intrinsic low expression levels of efflux systems and metabolizing enzymes in these tissues.
Additionally, and directly dependent on their bioavailability, the cost of these drugs, and particularly those needed for drug cocktails used for treatment of HIV/AIDS and cancer, both individually or combinations thereof, are prohibitive. This is particularly true for drugs where a vast quantity of the orally administered drug is either passed through the digestive system without entering the systemic circulation and excreted, or is at least partially metabolized and inactivated by the liver, before the drug gets to its intended target tissue.
Notwithstanding the above, to further complicate the treatments for HIV/AIDS and cancer, many of these drugs are also highly cytotoxic or have other undesirable secondary symptom such as irritating the GI system and therefore their quantity must be limited to minimum in order to prevent undesirable cytotoxic effects on other non-diseased tissues or prevent undesirable secondary symptoms, such as nausea, vomiting or other discomforts of the patients.
Thus it would be desirable to have available system that would augment systemic delivery of these cytotoxic, irritating, low bioavailability and/or expensive drugs and to permit use of lower dosages to obtain the same therapeutic effect.
Attempts have been made previously by inventors to provide an effective method and compositions for delivery of the chemotherapeutic drugs to female patients. Such efforts are described, for example, in the U.S. Pat. No. 6,982,091 issued on Jan. 3, 2006.
The previously disclosed methods provide an excellent means for delivery of drugs classified by BCS in Class I, having high intestinal membrane permeability and aqueous solubility. However, many of the currently used drugs as an anti-viral or anti-cancer treatment have low bioavailability due to their low aqueous solubility and/or low intestinal membrane permeability. Moreover, many of the Class II-IV drugs also show major GI toxicity and low oral absorption and although the vaginal delivery of these drugs described in the above cited patent application have considerably improved these symptoms, there is still a need for further improvements in their absorption and toxicity.
In addition to the therapeutic benefit of greater systemic exposure of anti-cancer and anti-viral drugs following buccal and vaginal administration, the methods described in this invention will also enhance topical treatment of neoplasia or pre-cancerous lesions present in the mucosae accessible via the oral and vaginal cavity. This includes epithelial dysplasia and invasive cancer of the female lower genital tract, such as cervical cancer and vaginal intraepithelial neoplasia, as well as oral squamous cell carcinoma. Epidemiologically, the prevalence of those malignancies correlates with chronic viral infections, particularly with subsets of the human papillomavirus (HPV) and cytomegalovirus (CMV), respectively (Ogura et al., Pathol. Int., 56: 301-308 (2006); Furrer et al., J. Oral Pathol. Med., 35, 338-344 (2006)). Therapeutic efficacy of anti-cancer and anti-viral drugs after oral administration is unsatisfactory in these cases because of limited systemic exposure. However, even after local drug administration, intracellular concentration of the pharmacological agent required for limiting HPV and CMV replication cannot be achieved as a result of highly active membrane efflux systems and metabolizing cytochrome P450 isozymes. Consequently, novel delivery approaches that increase intraepithelial drug concentrations in the infected oral or genital region are required to address this unmet medical need.
It is therefore, a primary object of this invention to provide a method for augmenting drug delivery of anti-viral and/or anti-cancer drugs into epithelial cells and/or into the systemic circulation by delivering such drugs to a subject in need thereof vaginally or buccally in an especially formulated composition increasing their therapeutic efficacy by providing means for increasing the drug solubility and permeability.
All patents, patent applications and publications cited herein are hereby incorporated by reference.